As for pharmaceutical products, drug delivery systems (DDS) that control the pharmacokinetics of physiologically active substances that serve as active ingredients and thereby deliver the physiologically active substances to specific sites of action in vivo at desired drug concentration-action times, have been developed. Non Patent Literature 1 describes a DDS preparation that employs a block copolymer in which a polyethylene glycol segment and a polyamino acid segment are connected together, as a drug delivery carrier. It is described that this block copolymer exhibits associative properties and forms a polymeric micelle configuration with a particle size of 20 to 100 nm, which has a polyethylene glycol outer shell and a hydrophobic inner core, and thus the block copolymer stably encloses various kinds of medicines in the inner core by means of chemical bonding or physical capture. This polymeric micelle type DDS preparation is characterized in that when the DDS preparation is administered in vivo, excretion thereof is suppressed so that retention in vivo is enhanced, and it is known that the DDS preparation migrates passively to tissues such as tumors and is accumulated therein. Therefore, by having a physiologically active substance retained in vivo for a long time period, availability of the active ingredient may be increased, and medicines that utilize these systems make it possible to successfully provide a stronger physiological activity effect compared to the loaded drugs.
In regard to the polymeric micelle type DDS preparation described above, preparations in which a medicine is incorporated into the inner cores of polymeric micelles through chemical bonding are known. For example, Patent Literature 1 describes a preparation example of a camptothecin derivative. Furthermore, Patent Literature 2 describes a preparation example of a resorcin derivative having HSP90 inhibiting activity, Patent Literature 3 describes a preparation example of a taxane derivative, and Patent Literature 4 describes a preparation example of a steroid derivative. Thus, these patent literatures disclose block copolymers conjugated with various physiologically active substances, which may be applied to various medicines.
Conventional physiologically active substance-conjugated block copolymers may increase blood retention of the conjugated medicines. Therefore, the medicines are caused to act for a long period of time on normal tissues as well as diseased tissues. For example, the block copolymer conjugated with a camptothecin derivative, an antitumor agent, which is described in Patent Literature 1, causes the camptothecin derivative to be dissociated in vivo in a release-controlled manner. As a result, the released camptothecin derivative is caused to act for a long period of time on normal tissues such as bone marrow as well as tumor tissues. For this reason, conventional camptothecin derivative-conjugated block copolymers exhibit a strong antitumor effect and also unavoidably manifest myelosuppression such as neutropenia, and this brings about dose limiting toxicity (DLT) (Non Patent Literature 2). Therefore, there is a demand for the development of a camptothecin derivative that exhibits further reduced myelosuppression while maintaining an antitumor effect. As such, conventional physiologically active substance-conjugated block copolymers are capable of exhibiting a strong pharmacological activity effect; however, there have been occasions in which those block copolymers exhibit adverse effects on normal tissues.
Accordingly, in regard to the above-mentioned polymeric micelle type DDS preparations, there is a demand for the development of a physiologically active substance-conjugated block copolymer that suppresses manifestation of a pharmacological activity function on normal tissues and exhibits reduced adverse effects while maintaining a physiological activity function-enhancing effect, which is a feature of the DDS preparation.